1. Field of the Invention
The present invention relates to imaging contrast agents, in particular, NMR imaging contrast agents.
2. Discussion of the Prior Art
It is well known to enhance NMR (nuclear magnetic resonance) images by, prior to conducting the imaging, introducing into the sample to be imaged ferromagnetic, diamagnetic or paramagnetic particles which shadow the image produced to intensify and contrast the image generate by the NMR sensitive nuclei. See, for example, the disclosures of U.S. Pat. Nos. 4,731,239; 4,863,715; 4,749,560; 5,069,216; 5,055,288; 5,023,072; 4,951,675; 4,827,945 and 4,770,183, the entire contents and disclosures of all of which are incorporated herein by reference.
A disadvantage associated with the use of NMR image contrast agents, however, resides in the fact that the internal magnetic properties of the various contrast agents employed heretofore affect the applied external field during the imaging process. These interactions of the paramagnetic or diamagnetic properties of the contrast agents with the applied external magnetic field give rise to irregularities in the resulting image, commonly referred to as imaging artifacts.
The application of magnetic resonance imaging (MRI) to abdominal imaging is potentially revolutionary, but currently is seriously limited by the inability to distinguish tumors, abscesses and other abnormalities from normal structures, e.g., bowel. As for computed tomography, the use of oral or rectal contrast agents is expected to dramatically improve the diagnostic value of MRI for abdominal diseases. Currently, superparamagnetic iron oxide (SPIO) is the best oral contrast agent available for use in MRI.
Iron oxide acts as a gastrointestinal (GI) MRI contrast agent primarily due to the dipolar interaction of the unpaired electrons of iron with the water protons in the body. In addition, its internal magnetization aligns parallel to an applied external field, increasing the magnetic field strength nearby. This is known as positive magnetic susceptibility, and also leads to large field gradients near the articles. Both of these mechanisms cause loss of signal intensity within the bowel. This loss of signal causes the desired enhancement of the difference in the appearance of bowel and other normal and abnormal structures in magnetic resonance images.
A problem with SPIO suspensions in the past has been that they not only affect the volume that actually contains the suspension (i.e., bowel), but also lead to artifactual signal loss in the region surrounding this area. This phenomenon is called susceptibility artifact and is more pronounced with greater field strength and with gradient recalled echo pulse sequences. This artifact reduces the diagnostic usefulness of SPIO, especially for gradient echo sequences which otherwise have many advantages for MRI of the abdomen.
Barium sulfate suspensions are also used as oral contrast agents for GI MRI. Barium sulfate is a diamagnetic substance; its paired electrons interact with an external magnetic field to produce internal magnetization oriented opposite to the applied field. This is known as negative magnetic susceptibility, and also produces loss of signal intensity due to diffusion of water molecules through the field gradients around the particles.
Imaging contrast agents which do not suffer from the above-noted disadvantages and a method of imaging which produces a substantially artifact-free image are described in U.S. Pat. No. 5,323,780 of which the present application is a continuation-in-part. Briefly, the improvements described in U.S. Pat. No. 5,323,780 related to a contrast agent useful for imaging a sample comprising a suspension in a medium acceptable for imaging (a) particles of a contrast agent possessing paramagnetic characteristics and (b) particles of a contrast agent possessing diamagnetic characteristics and a method of imaging a sample which comprises introducing into the sample the above-described contrast agent and generating a substantially artifact-free image thereof.
It has been found that the contrast agent suspensions described in U.S. Pat. No. 5,323,780 are subject to instability in that the components thereof tend to interact with each other and with the environments in which they are employed for magnetic resonance imaging such that the suspension of particles (a) and (b) destabilize and the particles "settle out" of suspension.
It is an object of the present invention to provide novel imaging contrast agents which do not suffer from the disadvantages associated with the agents described in U.S. Pat. No. 5,323,780, as well as a novel method of imaging which produces a substantially artifact-free image.